Key words epidermal growth factor receptor tyrosine kinase inhibitor-resistant anti-tumor
Basic research and clinical trials have confirmed that anti-epidermal growth factor receptor (epidermal growth factor receptor, EGFR, also known as HER 1, or cerbB 1) therapy can increase the effect of traditional chemotherapy drugs, and in some patients who acquire a partial response rate and stable disease efficacy. However, most patients do not from the benefits of this therapy, the reason these patients eventually performance of confrontation EGFR therapy resistance. This article intends to epidermal growth factor receptor tyrosine kinase inhibitor drug resistance mechanism and research progress are reviewed to provide a theoretical basis for clinical treatment.
An epidermal growth factor receptor tyrosine kinase inhibitor and its anti-tumor effect of EGFR to the first discovery of HER / cerbB 1 family of transmembrane receptor tyrosine kinase members of the family also includes HER 2 (cerbB 2), HER 3 (cerbB 3) and HER 4 (cerbB-4) . Tyrosine kinase inhibitors (tyrosine kinase inhibitors, TKIs) part of the quinazoline derivatives of the small molecule binding sites, blocking, by competing with ATP binding extracellular ligand intramolecular tyrosine autophosphorylation , inhibition of EGFR activation, thereby inhibiting cell cycle progression, accelerated apoptosis, inhibition of angiogenesis, inhibition of tumor invasion and metastasis. Gefitinib (Gefitinib, also known as ZD1839 or Iressa) as third-line monotherapy drug for advanced non-small cell lung cancer (non small cell lung cancer, NSCLC), erlotinib (Erlotinib, also known as OSI 774 or Tarceva ) as a standard in the treatment ineffective second-or third-line treatment of advanced NSCLC medication clinical effect [2,3]. However, studies have found that not all patients with high expression of EGFR can EGFR TKIs treatment response, these studies also found that some tumors initial response to treatment of Gefitinib treatment a few months later, however, the disease progression  , suggesting that the emergence of natural or secondary resistance.
2 EGFR tyrosine kinase inhibitor resistance mechanisms
EGFR tyrosine kinase inhibitors by multiple intracellular signal transduction pathways regulating tumor cell proliferation, survival, apoptosis, metastasis, invasion and tumor-induced angiogenesis. Dependent and non-dependent the EFGR signal transduction of tumor cells, several different molecular mechanism plays a very important role in the process of cell EGFR inhibitor-resistant. These molecular mechanisms are the following:
2.1 the activation of growth factor receptor bypass signal path
Genomic instability of tumor cells in a drug-induced selective pressure to start other survival mechanisms, to prevent necessary for cell survival signaling pathway was inhibited. These possible mechanisms, the insulin-like growth factor receptor 1 (insulin like growth factor receptor 1, IGF 1R) activation is one of them. Chakravarti A, et al  found that sensitive pleomorphic malignant glioma (glioblatoma multiforme, GBM) cell lines, EGFR inhibitor AG1478 induced apoptosis reduce its invasion ability; resistant GBM cell lines showed IGF 1R expression levels increased and sustained activation of the PI3K/Akt signaling pathway. United of IGF 1R inhibitor AG1024 and AG1478 EGFR inhibitors significantly increase GBM cell lines resistant to apoptosis and reduce the invasiveness. In addition, Jones et al , the study showed that, compared with Gefitinib-sensitive breast cancer cells TAM R, increased resistance to Gefitinib subline TAM / TKI R breast cancer cells IGF 1R activation, treatment with IGF 1R TKI AG1024 After Gefitinib increased sensitivity; similar to the breast cancer cell lines, Gefitinib-resistant subline DU145/TKI R prostate cancer IGF 1R activation increased. Hyperplasia  found of Gefitinib and IGF 1R inhibitor AG1024 alone can reduce several breast cancer cell lines (MDA468, MDA231, SK BR 3 and MCF 7); When the combination showed cell growth inhibition synergy. Of IGF 1R overexpression SK BR 3 cell lines resistant to Gefitinib significantly increase. This indicates that the the the IGF 1R signal can reduce the antiproliferative effect of Gefitinib several breast cancer cell lines; increase the anti-IGF 1R target the drug may be more effective than single Gefitinib Gefitinib treatment process. However Cappuzzo et al  by immunohistochemical methods in 124 cases of Gefitinib in NSCLC patients study found that IGF 1R expression associated with of Gefitinib the natural drug does not.
2.2 Non-dependent EGFR activation-induced tumor angiogenesis
Tumor cell-induced angiogenesis plays an important role in maintaining local tumor growth, invasion and metastasis. EGFR autocrine pathway regulates vascular endothelial growth factor (vascular endothelial growth factor, VEGF) and basic fibroblast growth factor (basic fibroblast growth factor, bFGF) generation. GEO colon cancer cells in nude mice in the allograft, chronic administration of EGFR inhibitors (Gefitinib or Cetuximab) to establish a drug-resistant the GEO subline. The initial EGFR inhibitors can inhibit the growth of tumor cells, the re-growth of the tumor cells after different incubation period can be seen in the inoculation site. In contrast, after treatment with 2 dual role of EGFR and VEGFR ZD6474, within a treatment period of up to 5 months, the growth of tumor cells is effectively suppressed. In addition, in the given Gefitinib or Cetuximab treatment given ZD6474 is also effective to inhibit tumor growth. Subsequent protein expression analysis showed that, compared with the parent cell line resistant cell lines EGFR expression levels did not change expression levels of VEGF increased from 5 to 10 times . This suggests that EGFR TKIs secondary resistance is not due to lack of EGFR expression, but because of the increase in VEGF levels. Therefore, the United EGFR and VEGF drugs that target may be an effective way to overcome EGFR TKIs resistance. However, Taguchi et al  found in an in vivo test, compared with Gefitinib and ZD6474 sensitive cell lines, resistance to of Gefitinib the lung adenocarcinoma cell line (PC 9/ZD) ZD6474 lack of sensitivity. This suggests that other non-dependent EGFR activation of biological pathways involved in tumor cell resistance phenotype appear.
2.3 EGFR gene mutation and the lack of targets
EGFR gene mutations caused by the absence of EGFR expression and function of the change may be a mechanism of tumor cells to EGFR tyrosine kinase inhibitor-resistant. Blencke et al  found that the EGFR tyrosine kinase domain of methionine instead of threonine 766, can significantly reduce the growth inhibition of tumor cells to PD153035 sensitivity. Learn et al  found that 40% of glioma expression EGFRv Ⅲ, while expressing GBM cell lines EGFRv Ⅲ only continuous exposure to higher concentrations of Gefitinib, phosphorylation can reduce. This indicates that the relative resistance of Gefitinib EGFRv Ⅲ-expressing cells.
Numerous studies indicate, however, point mutations in certain bits of EGFR tyrosine kinase domain such that the tumor cells to increased sensitivity to the EGFR. Zhang et al  studied the relationship between the treatment of advanced NSCLC patients EGFR mutations in Gefitinb of reaction. 98 patients, 12 cases effective gene mutations the reaction of Gefitinib in patients, as well as non-smoking, adenocarcinoma, a higher mutation rate of female patients, mutated patients compared with non-mutated patients overall survival time long. Shimato  EGFR mutations in patients with brain metastases Gefitinib efficacy of the relationship between the. 8 cases of the ago accept Gefitinib treatment of brain metastases in NSCLC patients, three cases effective in patients with Gefitinib treatment have emerged tyrosine kinase domain of EGFR mutations (two cases for the deletion mutation, point mutations) three cases of invalid patients found no mutation appears. This suggests that the efficacy of Gefitinib for NSCLC brain metastasis have a certain relationship with the EGFR mutation. Takano et al  study of 66 patients with recurrent NSCLC patients found that 39 patients (59%) patients with EGFR mutations; including 20 patients with exon 19 point performance for the deletion mutation; 17 patients outside exon 21 point missense mutation (L858R), 2 patients with nonsense mutations (G719S or G719C) outer exon 18 points; NSCLC patients with EGFR exon 19 deletion given Gefitinib or Erlotinib treatment with L858R point mutation NSCLC longer survival time compared with patients with a response rate of 73% and 50%, respectively; Progress improved time for 24 months and 10 months respectively. These studies suggest that it is precisely because the missing gene mutations in EGFR domain sites or point mutation makes the tumor cells become resistant to EGFR inhibitors.
2.4 EGFR downstream signal transduction pathways sustained activation
The phosphatase PTEN / MMAC / TEP (PTEN) function missing and sustained activation of Akt pathway also played a certain role in the process become resistant to EGFR inhibitors.
PTEN is a lipid phosphatase and regulation of the PI3K/Akt pathway tumor suppressor protein, PTEN function missing cause excessive activation of the Akt pathway, thereby increasing cell resistance to apoptosis. Ueda et al  found that in vivo research on three kinds of hepatocellular carcinoma cell line (HCC3, CBO12C3, and AD3), Gefitinib can inhibit these three cell lines Akt phosphorylation, but its inhibitory AD3 cell lines effect to be low, compared to the same HCC3 CB012C3 cell strain AD3 cell strain of PTEN concentration lower half; PTEN small interference RNA (small interfering RNA, siRNA) transfection HCC3 cell lines can be reduced such cells Gefitinib Inhibition sensitivity. Wang et al  reported that 40% to 50% of malignant glioma cell performance PTEN deletion, mammalian target of rapamycin body (mammalian target of rapamycin, mTOR) inhibitor rapamycin can improve PTEN deletion the sensitivity of tumor cells to EGFR kinase inhibitor Erlotinib. United EGFR / mTOR kinase inhibitors can inhibit both U87MG and SF295 growth of tumor cells of malignant glioma cell lines, and inhibition of downstream PI3K signaling pathway has an additive effect. Reconstruction PTEN function can re-establish a dependent EGFR activation of Akt signaling pathway, thereby restoring the sensitivity of these cells to ZD1839. Although the reconstruction of the tumor cells, PTEN function is difficult to implement in clinical practice, but the absence of PTEN to promote excessive activation of the PI3K/Akt signaling pathway, and this activation energy by drug regulation. Thus PI3K/Akt pathway inhibitor LY294002 down PI3K/Akt signaling pathway to restore EGFR activation of Akt signaling pathway, MDA 468 cells of ZD1839 sensitivity .
Sustained activation of PI3K/Akt pathway plays an important role in the process of resistance to EGFR inhibitors. Ihle et al  found that the PI3 K signaling pathway inhibitor PX 866, to increase the reactivity of the NSCLC patients with EGFR inhibitors such as Gefitinib. Studies have shown Gefitinib inhibition height of EGFR activation in breast cancer cell lines (SK BR 3), moderate (MDA MB 361) and Low (MDA-MB 468), but to high, moderate sensitivity two groups P42/p44 MAPK and AKT activation was significantly reduced . PI3K inhibitor LY294002 or MEK inhibitor PD98059 could significantly inhibit the growth of MDA MB 468 cell lines. Consistent with this finding: PD98059 and Gefitinib MDA MB 468 cells has a synergistic effect, while the other two cell lines have a cumulative effect. Compared with single-agent, both joint MDA-MB 468 cell lines increased apoptosis. This phenomenon is the same MAPK activation and reduced BAD (ser112) phosphorylation and AKT activation is associated with increased. This suggests that Akt might be a major anti-EGFR therapy resistance factor.
Recent research has found to carry a gene amplification of cyclin D1 (Cyclin D1) and (or) protein overexpression in patients with head and neck squamous cell carcinoma showed Gefitinib resistant . E cadherin transfected into Gefitinib-resistant cells, can significantly increase the resistant cell lines of of Gefitinib the sensitivity . Therefore, histone deacetylase inhibitor MS 275 with Gefitinib may be overcome lung cancer patients resistant to EGFR inhibitors, a new drug therapy. Head and neck squamous cell carcinoma in the United Gefitinib and ErbB2 target antibody pertuzumab cumulative growth inhibition, and this growth inhibition than with Gefitinib Gefitinib resistant HNSCC cell lines . This study shows that the other members of the EGFR / erbB family easier than EGFR resistance Gefitinib produce.
In short, as a promising anticancer drugs, EGFR TKIs secondary the drug generation is a difficult problem to clinical problems. The present study suggests that a variety of molecular mechanisms involved in the drug generation, these resistance mechanisms, to joint some other targeted drugs may be a more effective tumor treatment.